Automatic devices for remote ischemic preconditioning

ABSTRACT

Single- or dual-bladder devices for remote ischemic preconditioning and blood pressure monitoring are disclosed along with various oscillometry-based and other methods for detecting systolic and diastolic blood pressure while the ischemic preconditioning treatment is in progress. The devices and methods of the invention provide for delivery of ischemic preconditioning at the lowest effective cuff pressure while closely monitoring patient&#39;s hemodynamics. Advantageously, the device of the invention allows both ischemic preconditioning and blood pressure monitoring to be done on the same limb. Disposable battery-powered version of the device of the present invention is especially useful for emergency use with patients suffering from acute myocardial infarction, acute stroke, or acute trauma. Additional device configurations are described for use in a percutaneous intervention and vascular sealing settings.

CROSS-REFERENCE DATA

This application is a continuation of my U.S. patent application Ser.No. 12/820,273 entitled “METHODS AND DEVICES FOR REMOTE ISCHEMICPRECONDITIONING AND NEAR-CONTINUOUS BLOOD PRESSURE MONITORING” filedJun. 22, 2010, now U.S. Pat. No. 8,114,026 which in turn claims apriority benefit from the U.S. Provisional Patent Application No.61/219,536 filed Jun. 23, 2009 entitled “BLOOD PRESSURE CUFFINCORPORATING A PRECONDITIONING DEVICE” and the U.S. Provisional PatentApplication No. 61/256,038 filed Oct. 29, 2009 entitled “PRECONDITIONINGDEVICES FOR USE IN AMI AND PERCUTANEOUS INTERVENTION SETTINGS”, allthree documents incorporated herein by reference in their entireties.

BACKGROUND OF THE INVENTION

The present invention relates generally to methods and devices aimed atreducing a harmful effect of ischemia and reperfusion injury of an organwith the overall purpose of reducing the final infarct size and loss offunction by the organ. More particularly, the invention describesmethods and designs for blood pressure cuffs configured to deliverremote ischemic preconditioning and monitor blood pressure of thepatient.

Coronary heart disease is a leading cause of mortality and morbidity inthe Western world and is projected to be a leading cause of deathworldwide by year 2020. Acute myocardial infarction (AMI) is the maincause of such mortality. Although major advances in treatments over thelast four decades have translated into a considerable decline inmortality rates after AMI, heart failure became a common complicationfor survivors, with the estimated post-infarct incidences between 10%and 40%. Post-infarct heart failure is a debilitating disease associatedwith high mortality, with a median survival of only 4 years. In theUnited States, the American Heart Association estimates the total numberof patients living with heart failure today to be 5.3 million with 660thousand new patients diagnosed every year. Direct and indirecttreatments for these patients cost approximately $35 billion a yearrepresenting the single highest disease burden of all healthcare costs.

In patients with acute myocardial infarction, rapid restoration of bloodflow (reperfusion) either by primary percutaneous coronary interventionor thrombolysis is the most effective treatment for myocardial salvage.However, it has now been shown that reperfusion itself has the potentialto induce additional lethal injury that is not present at the end of theischemic period. This injury is called an ischemia/reperfusion injury orsimply a reperfusion injury. Reperfusion injury is a contributing factorin many other diseases, most notably including acute stroke, acutetrauma, acute compartment syndrome, etc. Management of planned ischemiaevents during CABG, AAA and other types of surgery may also benefit fromreducing the consequences of reperfusion injury.

A new treatment to induce ischemic tolerance and reduce the harmfuleffects of reperfusion injury is known as ischemic preconditioning.Other terms used in the literature to describe this intervention include“ischemic postconditioning”, “ischemic perconditioning”, and “ischemicconditioning”. For the purposes of this description, all proceduresdescribing a series of sub-lethal interruptions of blood flow aredescribed using the general term “ischemic preconditioning” whether itis done prior to, during, or after the ischemia as well as prior to,during, or after reperfusion. Remote ischemic preconditioning describesone version of this treatment, which includes applying a series of briefsub-lethal episodes of ischemia and reperfusion to an organ other thanthe target ischemic organ (such ischemic organ may be a heart or abrain). This treatment triggers activation of Reperfusion Injury SalvageKinases (RISK) pathways as well as strong anti-apoptosis andanti-inflammatory effects. Applying a series of brief ischemic stimulaeto a distant organ before, during, or after restoration of normalperfusion of the target ischemic organ is shown to activate protectionfrom ischemia for the whole body and therefore reducesischemia-reperfusion damage of the target organ. Over the years, anumber of distant organs have been shown to provide cardioprotection inthe setting of remote ischemic preconditioning including skeletalmuscles on upper and lower extremities. Applying a preconditioningprocedure externally to an upper or lower limb is especially attractiveas it is non-invasive, easy to implement, and safe. Blood flow to thelimb during the procedure is typically occluded for 3-5 min by amanually- or automatically-inflated blood pressure cuff or a tourniquetcuff. A deflation interval of 3-5 min then follows and this cycle isrepeated 3-4 times. An overview of this procedure and the mechanisms ofaction are described for example by Kharbanda R K, Nielsen T T, andRedington A N. “Translation of remote ischemic preconditioning intoclinical practice”, Lancet 374:1557-1565, 2009, incorporated herein byreference in its entirety.

Although the following description discusses applying remote ischemicpreconditioning to a subject or patient (both terms are used to mean thesame for the purposes of this specification) suffering from acutemyocardial infarction to reduce infarct size, it is not limited to thisclinical application alone. As mentioned above, this treatment can beapplied to acute stroke and trauma patients including those sufferingfrom traumatic brain injury, as well as to patients during, prior orafter various interventions or surgeries when blood flow to an organ istemporarily interrupted or a release of embolic particles is likely.They can also be applied in organ and tissue transplant surgeries aswell as in other clinical applications.

U.S. Pat. No. 7,717,855 to Caldarone et al. incorporated herein byreference in its entirety discloses one example of an automatic deviceconfigured to deliver remote ischemic preconditioning by periodicinflation and deflation of a cuff placed about a limb of a patient.Blood flow through the limb is interrupted by inflating the cuff to aset pressure above the systolic blood pressure of the patient. One sitedexample of such set pressure is 200 mmHg. This approach has a limitationin that inflating the cuff to such high pressure for extended periods oftime may cause pain and discomfort to the patient. For most of thepatients, there is no need to inflate the cuff to 200 mmHg to achievetotal limb occlusion. On the other hand, in a small portion of thepatients with high or rapidly changing blood pressure (with systolicblood pressure exceeding 200 mmHg), the set inflation pressure approachmay not be sufficient to occlude the limb adequately.

Patients suffering from an acute myocardial infarction or stroke requireclose monitoring of their vital signs and blood pressure in particular.Deterioration of blood pressure may cause profound ischemia andmulti-organ failure. Emergency medicine guidelines recommend checkingpatient's blood pressure every 3-5 minutes especially afteradministering vasodilators such as nitroglycerin. It is envisioned thatupon a first contact with a medical practitioner and confirmation ofdiagnosis, a heart attack patient would need initiation of ischemicpreconditioning and vital signs monitoring almost at the same time.Occupying one arm with a preconditioning cuff will require using anotherarm for a traditional blood pressure monitoring cuff. This two-armarrangement is not only cumbersome but may also cause interruption ofintra-venous injections during the periods of blood pressuremeasurements when the cuff is inflated and occludes blood flow to thearm.

It is therefore desirable to frequently monitor blood pressure for signsof hemodynamic deterioration and conduct ischemic preconditioning on thesame arm, leaving the second arm for uninterrupted intra-venousinjections. The need also exists for a device capable of deliveringpreconditioning at the lowest possible cuff pressure so as to reducepatient's discomfort and pain.

SUMMARY OF THE INVENTION

According to one aspect of the invention, devices and methods for remoteischemic preconditioning treatment are provided. The treatment protocolincludes at least one or preferably 3 to 5 treatment cycles; each cycleincludes intervals of cuff inflation, an ischemic duration lasting forat least about a minute, cuff deflation, and reperfusion duration. Thecuff of the device is maintained at a minimum inflation pressure, whichmay be at or below the systolic blood pressure of the subject. To assureat least a substantial reduction or preferably a total cessation ofblood flow through the limb during the ischemic duration, the cuffinflation pressure may be maintained at a level at or above the limbocclusion pressure. The width of the cuff is selected to be sufficientlywide so as to define the limb occlusion pressure to be below thesystolic blood pressure of the subject.

Maintaining the cuff in a minimum limb occlusion state (defined bykeeping the cuff pressure at or above the limb occlusion pressure andbelow the systolic blood pressure) during at least a portion of theischemic duration interval allows to minimize subject's pain anddiscomfort while at the same time providing a unique opportunity tomonitor subject's systolic blood pressure without allowing forreperfusion of the limb.

In another aspect of the invention, the remote ischemic preconditioningdevice is provided to include a cuff and a controller configured toinflate and deflate the cuff according to a preconditioning treatmentprotocol, the controller is further configured for hemodynamicsurveillance during and in parallel with the preconditioning treatmentprotocol. The hemodynamic surveillance includes at least once detectingsystolic blood pressure during an ischemic duration interval when thecuff pressure is maintained between the limb occlusion pressure and thesystolic blood pressure of the subject. The hemodynamic surveillance mayfurther include at least once detecting diastolic blood pressure duringthe limb reperfusion duration interval. In another aspect of theinvention, systolic and diastolic blood pressures are determinedperiodically, on a frequent or a near-continuous basis.

Various methods may be employed to detect systolic blood pressure whilethe cuff is at a minimum limb occlusion state. For example, Korotkoffsounds may be detected by various sensors incorporated into the cuffsuch as a microphone. Another method is to measure a portion of theoscillometric envelope curve in the vicinity of the systolic pressure.If a deviation of the curve from that which is previously measured isdetected, a new systolic blood pressure value may be determined bymatching the pulsations amplitude to that corresponding to a previouslydetected value of systolic pressure. The pressure range defining theminimum limb occlusion state is then adjusted. Other methods may also beused to determine the current value of systolic blood pressure from theoscillometric envelope such as for example a derivative oscillometrywhere the systolic pressure is defined by a maximum of the firstderivative of the oscillometric envelope curve. The portion of thatcurve may be continuously of periodically updated by dithering orvarying the cuff pressure about the previously detected value ofsystolic blood pressure—all without compromising occlusion of the limb.

According to another aspect of the invention, the cuff of the deviceincludes more than one bladder, such as for example a first and a secondbladder. In another embodiment of the invention, the first bladder isdesignated as a proximal bladder and the second bladder is designated asa distal bladder. For the purposes of this description, the termproximal refers to that closer to the heart while the term distal refersto that closer to the periphery of the circulatory system. In case of alimb of a subject being an upper arm for example, the proximal bladderwould be that located above the distal bladder. Having more than onebladder located adjacent to one another and having the samecircumference allows a great deal of flexibility in operating the cuffof the invention. For example, to detect the current value of systolicblood pressure, the proximal cuff may be used to gradually decrease thepressure applied to the limb, while the distal cuff may be used fordetecting a rapid or abrupt increase in pulsations amplitude indicatingthat the proximal cuff pressure has reached the systolic blood pressurevalue. At other times, both bladders may be inflated to the samepressure, providing in essence the limb occluding function of a widercuff.

In another aspect of the invention, a device for remote ischemicpreconditioning includes a cuff configured to retract about a limb of asubject, the cuff having an inflated state to reduce blood flow throughthe limb and a deflated state. The device further includes a controllerconnected to the cuff and including a first inflation assemblyconfigured to inflate and deflate the cuff to the inflated state and thedeflated state respectively according to a preconditioning treatmentprotocol. The treatment protocol includes a plurality of treatmentcycles, each cycle comprising: cuff inflation, an ischemic duration,cuff deflation, and reperfusion duration. The controller furtherincluding a port for attaching a second inflation assembly adapted formeasuring blood pressure of the subject through the cuff. The controlleris further configured to connect the port to the cuff only during thecuff deflation and reperfusion duration periods of at least one of thetreatment cycles. The second inflation assembly may include a manualinflation bulb or a non-invasive blood pressure monitor.

In a further aspect of the invention, the device for remote ischemicpreconditioning includes a first cuff configured to retract about a limbof a subject, the first cuff having an inflated state to reduce bloodflow through said limb and a deflated state. The device further includesa controller connected to the first cuff and including a first inflationassembly configured to inflate and deflate the first cuff to theinflated state and the deflated state respectively according to apreconditioning treatment protocol including a plurality of treatmentcycles, each cycle comprising the first cuff inflation, an ischemicduration, the first cuff deflation, and a reperfusion duration. Thedevice further including a second cuff configured to measure bloodpressure of the subject on the same limb as used for ischemicpreconditioning treatment. The controller is further optionallyconfigured to measure the subjects' blood pressure via the second cuffduring deflation of the first cuff or reperfusion duration intervals ofat least one of the treatment cycles.

In a further aspect of the invention, the controller is battery-poweredand incorporated with the preconditioning cuff of the device. In yetanother aspect of the invention, the device includes a countdown timerof a predetermined interval of time such as 2 hours upon a completion ofthe preconditioning treatment protocol. In yet another aspect of theinvention, the remote ischemic preconditioning device includes a sterilecover sized to completely wrap about the cuff while on the limb of thesubject.

In another aspect of the invention, the remote ischemic preconditioningdevice is provided, the device comprising a cuff configured to retractabout an upper arm of a subject, the cuff including a bladder having aninflated state to reduce blood flow through the upper arm and a deflatedstate, a controller connected to the bladder and including an inflationassembly configured to inflate and deflate the bladder to the inflatedstate and the deflated state respectively according to a preconditioningtreatment protocol. The treatment protocol includes a plurality oftreatment cycles, each cycle comprising: cuff inflation, an ischemicduration, cuff deflation, and a reperfusion duration. The inflationassembly is further configured to complete the cuff inflation in 30seconds or more. In another aspect of the invention, the inflationassembly includes an air pump with flow rate less than about 0.1 cubicfeet per minute.

In a further aspect of the invention, the automatic remote ischemicpreconditioning device is provided as described above, the controllercontaining a single START button operable to initiate the ischemicpreconditioning treatment, the controller further configured to conductand finish the entire treatment protocol without further user input.

In yet another aspect of the invention, there is provided a remoteischemic preconditioning device comprising a cuff configured to retractabout a limb of a subject and including one or two bladders having aninflated state to reduce blood flow through said limb and a deflatedstate. The device further includes a controller connected to these oneor two bladders and including an inflation system configured to inflateand deflate the bladders to the inflated state and the deflated staterespectively according to a preconditioning treatment protocol describedabove. The controller is further configured to inflate these one or twobladders in incremental steps by reaching predetermined pressure levelswith an optional pause at each pressure level to determine the presenceor absence of heart beats in the limb. The final pressure level isidentified once the absence of heart beats is detected.

In a further yet aspect of the invention, provided is a combinationremote ischemic preconditioning and vascular sealing device comprisingan occluding bulb configured to occlude a major artery of a subject, thebulb having an inflated state and a deflated state. The device furtherincludes a retaining means to position and retain the occluding bulbover an arteriotomy in said major artery. The device further comprises acontroller connected to the bulb and including an inflation assemblyconfigured to inflate and deflate the bulb to the inflated state and thedeflated state respectively according to a preconditioning treatmentprotocol described above. The controller is further configured toinflate the bulb according to a vascular sealing protocol. In anotheraspect of the invention, the vascular sealing protocol includes a firstduration when the major artery is occluded, a second duration when bloodflow in the major artery is at least partially restored and a thirdduration when blood flow in the major artery is completely restored.

In yet a further aspect of the invention, a device for remote ischemicpreconditioning and vascular sealing is provided. The device comprises avascular sealing subassembly with an occluding bladder configured toprovide hemo stasis of an arteriotomy in a femoral artery of a subject.The device further comprises a preconditioning cuff configured toretract about a thigh of the subject and including a cuff bladderincorporated therein having an inflated state to reduce blood flow inthe thigh and a deflated state. The device further comprising anattachment means between the sealing subassembly and the preconditioningcuff to position and retain the occluding bladder over the arteriotomy.In a further aspect of the invention, the attachment means having afirst state to position the deflated sealing bladder about thepreconditioning cuff and a second state to extend the occluding bladderto the arteriotomy. In another aspect of the invention, the devicefurther includes a controller configured to inflate and deflate thepreconditioning cuff according to the treatment protocol as describedabove and further adapted to inflate and deflate the occluding bladderaccording to a vascular sealing protocol. In a further aspect of theinvention, the vascular sealing protocol includes detection of at leastone of complete artery occlusion condition, partial flow condition andfull flow condition by monitoring pressure in a partially inflatedbladder of a preconditioning cuff.

In yet another aspect of the invention, an introducer sheath is providedincluding a hub with a sheath tubing extending therefrom, the introducersheath configured to be insertable into a blood vessel and furtherincluding an expandable balloon positioned on the tubing and defining aninflated state to reduce or occlude blood flow in the blood vessel of asubject and a deflated state, the sheath further including an inflationlumen connected to said balloon. In a yet further aspect of theinvention, the introducer sheath further includes a controller toinflate and deflate the balloon to the inflated state and the deflatedstate respectively according to a preconditioning treatment protocolincluding a plurality of treatment cycles, each cycle comprising ballooninflation, an ischemic duration, balloon deflation, and a reperfusionduration. In a further aspect of the invention, the introducer sheathincludes a blood pressure indicator comprising an air chamber with avisible window and a blood pressure lumen extending therefrom to anopening located in the artery adjacent to the balloon.

BRIEF DESCRIPTION OF THE DRAWINGS

A more complete appreciation of the subject matter of the presentinvention and the various advantages thereof can be realized byreference to the following detailed description in which reference ismade to the accompanying drawings in which:

FIG. 1 is a general illustration of the device of the present invention;

FIG. 2 is a general chart of cuff pressure used in a traditionaloscillometric method of measuring blood pressure disclosed in the priorart;

FIG. 3 is a chart illustrating measuring systolic blood pressure andinflating/deflating the cuff of the device during the preconditioningtreatment protocol of the invention;

FIG. 4 is a block-diagram of the device according to one aspect of theinvention;

FIG. 5 is a general illustration of the preconditioning device of theinvention where the cuff includes a proximal and a distal bladder;

FIG. 6 is a block-diagram of the air handling elements and cuffinflation assembly of the device according to another aspect of theinvention in which the device includes a dual-bladder cuff;

FIG. 7 is a schematic illustration of the device of the inventionconfigured for use during a percutaneous catheterization procedure;

FIG. 8 is a side view of the device shown in FIG. 7;

FIGS. 9A and 9B are collapsed and extended schematic illustrations ofone specific embodiment of the device of the invention configured forperforming both ischemic preconditioning and vascular sealing functions;

FIG. 10 is an illustration of another device adapted for the samepurpose as that shown in FIGS. 9A and 9B; and

FIG. 11 is a side view of yet another device of the invention, namely anintroducer sheath with a built-in balloon to provide an ischemicpreconditioning functionality.

SINGLE-BLADDER DEVICE FOR REMOTE ISCHEMIC PRECONDITIONING

To facilitate prompt patient care and reduce ischemic damage, remoteischemic preconditioning may be initiated at the first signs of AMI. Atthe same time, care should be taken to assure reperfusion within abouttwo hours following the completion of the preconditioning treatmentprotocol as its efficacy may be reduced thereafter. The first contact bya medical professional with a subject suffering an AMI can occur in theEmergency Department or when paramedics arrive at the subject'slocation. Once a preconditioning device is placed on an upper arm (or aleg) of the subject and the preconditioning treatment is initiated, itmay take 3-4 cycles of about 3-5 min inflation and 3-5 min deflationintervals for the procedure to be completed, making the entire treatmentoccurring over 30 to 40 min period of time. Importantly, during thattime, the subject may be delivered by the ambulance to the EmergencyDepartment of hospital and then further moved to a cathlab or a surgicalsuite. Leaving the preconditioning device on the patient throughoutmoving the subject from one hospital department to the next presents alogistical problem as the ambulance personnel has to leave thepreconditioning device behind with each subject or alternatively notifythe next medical person of the stage of preconditioning treatment.

FIG. 1 illustrates a general illustration of the preconditioning device100. It includes a cuff 110 and a controller 150 incorporated therewith.Either the cuff or the controller may be made disposable or reusable.FIG. 1 shows one particular version of the device in which thecontroller 150 is battery-powered and integrated with the cuff. Theentire device is designed for a single-time use. The novel device of theinvention may be a low-cost all-in-one disposable cuff with anintegrated controller. It is designed to be placed as one piece on thesubject's upper arm or a thigh. The device may be advantageouslydesigned to automatically conduct a remote preconditioning treatmentprotocol with a push of a single START button. No additional componentsof the device have to be placed elsewhere or supported at a locationother than the arm or a thigh of a subject. This configuration isadvantageous for use in emergency circumstances described above such aswith a subject suffering from an acute heart attack, acute stroke, oracute trauma. In these situations, an all-in-one disposable automaticdevice is preferred because it allows for easy and rapid subjecttransfer during the course of preconditioning treatment from ambulanceto emergency department and then to another department in the hospital.Because of its simplicity and automatic nature, there is no need to havea dedicated person to stay with the patient throughout thepreconditioning treatment to ensure its proper timing. There is also noneed to track and retrieve reusable components of the device after thetreatment is complete—the entire device is simply disposed of after theprocedure is finished. Another advantage of a fully disposable device isthat it can be easily provided in sterile condition—this is advantageousfor treating or pre-treating patients undergoing various surgery orpercutaneous interventions.

According to other embodiments of the invention, controller 150 may belocated at a location other than the cuff: it can be a stand-alone unitor be a part of a comprehensive multi-purpose medical apparatus such asfor example a comprehensive vital signs monitor.

The cuff 110 of the device includes or incorporates a bladder 112 (FIGS.1 and 4) of a generally rectangular shape. Dimensions of the cuff andbladder may generally follow the standards established for bloodpressure measurement cuffs, as described for example in the article byPickering T G et al. entitled “Recommendations for Blood PressureMeasurement in Humans and Experimental Animals. Part 1: Blood PressureMeasurement in Humans”, Hypertension 2005; 45:142-161. Anotherpublication defining standard cuff sizes is an article entitled “HumanBlood Pressure Determination by Sphygmomanometry” published by AmericanHeart Association, 1993. Both articles are incorporated herein in theirentirety by reference. In particular, the standard cuff may have abladder length that is 80% and a width that is about 40% to 46% of armcircumference (a bladder length-to-width ratio of about 2:1). Therecommended standard cuff sizes are: for arm circumference of 22 to 26cm—the cuff should be “small adult” size, 10-12 cm wide by 22 cm long;for arm circumference of 27 to 34 cm—the cuff should be “adult” size,13-16 cm wide by 30 cm long, for arm circumference of 35 to 44 cm—thecuff should be “large adult” size, 16 cm wide by 36-38 cm long, and forarm circumference of 45 to 52 cm—the cuff should be “adult thigh” size,16-20 cm wide by 42 cm long.

One advantage of having the cuff and the bladder for the device of theinvention having the standard sizes shown above is that the device mayinclude an optional side port (not shown) which can be attached to amanual or automated blood pressure measurement device such as a patientmonitor. The device of the invention may in that case be additionallyused for manual or automatic standard blood pressure measurement before,during, or after the preconditioning treatment protocol. The controllermay also be optionally adapted to allow this side port to be connectedwith the cuff bladder only during the reperfusion duration so as not tointerfere with the efficacy of the preconditioning treatment protocolwhen the cuff is in the inflated state during the ischemic durationinterval. The details of such device are disclosed in the above cited'536 and '038 provisional patent applications.

At the same time, as described above, there is a need to have anischemic preconditioning device allowing for effective preconditioningtreatment at the lowest possible cuff pressure applied during theischemic duration interval. This may be achieved by utilizing theobservation that the pressure needed for occluding the limb and reducingmost or all blood flow through the limb (called herein a limb occlusionpressure) depends on a number of factors and does not necessarily haveto be greater than the systolic blood pressure of the subject. Limbischemia sufficient for ischemic preconditioning purposes is producedwhen the blood flow through the limb is at least substantially reducedor preferably entirely stopped. A reduction of about 90% or greater isbelieved to be sufficient to cause therapeutic effects of ischemicpreconditioning. For the purposes of this description, the term “limbocclusion” encompasses limb conditions when the blood flow therethroughis reduced by at least 90% or more. The term “limb occlusion pressure”is used herein to define the condition of limb occlusion as explainedabove.

According to one aspect of the invention, in order to define the limbocclusion pressure to be at or below the systolic blood pressure of thesubject, the width of the cuff is selected to be at or greater thanabout ⅓ of the arm circumference for which the length of the cuff isappropriately selected. Given the standard ranges of cuff sizes, thewidth of the cuff may be selected to be as follows: small adult—at least9 cm, adult—at least 12 cm, large adult—at least 15 cm, and adultthigh—at least 18 cm.

Blood pressure monitors are known to measure blood pressure with acertain small measurement error, typically a few millimeters of mercury.To avoid partial limb reperfusion when the systolic blood pressure ismeasured inaccurately, the cuff of the device is provided with a widthsufficient to assure a limb occlusion pressure to be well below thesystolic blood pressure of the subject, typically by 5-10 mmHg. Toassure the condition of limb occlusion when the cuff is placed in aminimum limb occlusion state (defined by a cuff pressure to be about orgreater than the limb occlusion pressure but not exceeding the systolicblood pressure of the subject), the width of the cuff may be increasedby at least 3 cm or preferably 5-10 cm as compared to the above statedstandard widths. The ratio of width to arm circumference for oneconfiguration of the device is selected to be about 0.4 or greater. Inanother configuration, the width to arm circumference ratio is at orabove 0.5. Given the standard sizes of the cuff described above andtaking into account the preference to make them wider to reduce limbocclusion pressure but without exceeding the length of the limb, thewidths of the cuffs of the device are as follows: small adult—12-19 cm,adult—16-22 cm, large adult—16-25 cm and adult thigh—20-25 cm. Cufflengths are selected to match that of standard cuffs as described above.

For example, making the cuff width at 15 cm for a small adult cuff and18 cm for an adult cuff would define the limb occlusion pressure to beequal to a sum of 0.6 P_(SYS)+0.4 P_(DIA). Given a typical bloodpressure of 110 mmHg over 80 mmHg, using such cuff will result in a limbocclusion pressure being about 98 mmHg. Maintaining the cuff pressure ata minimum limb occlusion state from about 98 mmHg to about 110 mmHg willproduce limb occlusion at a reasonably comfortable cuff pressure for thesubject.

Calculations for large adult and adult thigh are slightly different. Ina typical example, making the large adult cuff 21 cm wide and adultthigh cuff 25 cm wide would define the limb occlusion pressure to beequal to a sum of 0.7 P_(SYS)+0.3 P_(DIA). Given the same typical bloodpressure of 110 mmHg over 80 mmHg, using such cuff will result in a limbocclusion pressure being about 101 mmHg—still providing a wide enoughmargin for a pressure range of the minimum limb occlusion pressures ofthe cuff.

The central processing unit of the controller 150 may be programmed tocause the cuff inflation system to bring the cuff to the minimum limbocclusion state at least once or, in other embodiments, on a periodicbasis (such as for example every minute or so) during at least a portionof the ischemic duration of the preconditioning treatment protocol. Tofurther reduce pain and discomfort of the subject, the controller 150may be programmed to maintain the cuff pressure between the limbocclusion pressure and the systolic blood pressure of the subjectthroughout the entire ischemic duration interval.

To achieve this objective, it is important to accurately and frequentlydetect the value of the systolic blood pressure of the subject. Thedevice of the invention is devised to provide for such accurate andfrequent determination of the systolic blood pressure while the cuff isplaced in the minimum limb occlusion state. One advantage of the deviceof the invention is that the systolic blood pressure may be determinedfrequently but without compromising limb occlusion and thereforejeopardizing the therapeutic effect of the ischemic preconditioning.

One proposed method of detecting and frequently updating the value ofsystolic blood pressure of the subject is based on a novel modificationof oscillometric method of blood pressure measurement. Traditionally,during the oscillometric blood pressure measurement, the cuff isinflated to a pressure above the previously measured or estimatedsystolic blood pressure of the subject. The cuff is then graduallydeflated with a deflation rate of 2-5 mmHg per second while thecontroller is configured to record the cuff pressure. FIG. 2 contains atypical recording of cuff pressure during the procedure of bloodpressure measurement. Increased pulsations are observed on the cuffpressure curve in the area generally between the values of systolic anddiastolic blood pressures. The principles of oscillometric determinationof blood pressure are explained in detail in the prior art publications,for example in an article by G. Drzewiecki et al. entitled “Theory ofthe oscillometric maximum and the systolic and diastolic detectionratios”, Annals of Biomedical engineering, 22:88-96, 1994 incorporatedherein in its entirety by reference. Cuff pressure pulsations areextracted from the cuff pressure curve and converted into a separatecurve of pulsation amplitude vs. time. This curve is referred to as anoscillometric envelope. Typically, as the cuff pressure is beinggradually reduced, the amplitude of cuff pulsations is increasing oncethe cuff pressure is below systolic blood pressure of the subject. Theamplitude of pulsations reaches a maximum at a mean arterial pressureand then gradually declines past the point of diastolic blood pressure.One typical example of an oscillometric envelope is shown in FIG. 3.Recording a full oscillometric envelope allows measuring of the meanarterial pressure at the cuff pressure curve at the point correspondingto A_(MAX) which is the maximum amplitude of the oscillometric envelopecurve. The values of systolic and diastolic blood pressures are thendetermined using empirically-derived predetermined ratios. The maximumamplitude A_(MAX) is multiplied by a systolic ratio of about 0.55 andthe amplitude point A_(SYS) on the oscillometric curve where theamplitude is that of 0.55 times A_(MAX) is used to look up the cuffpressure which is then declared to be a systolic blood pressure of thesubject. Diastolic blood pressure is determined at the amplitude pointof A_(DIA) where the amplitude of pulsations is that of A_(MAX)multiplied by a diastolic ratio of about 0.85—see FIG. 3.

Recording cuff pressure may be done using a pressure sensor andextracting a full oscillometric envelope from the signal derivedtherefrom. This may be done on gradual cuff deflation or gradual cuffinflation. Using cuff deflation method allows an advantage of a pressuresignal not contaminated by the noise introduced by an air pump. On theother hand, using cuff inflation method allows not overinflating thecuff beyond the systolic blood pressure. Both cuff inflation and cuffdeflation methods may be used for the purposes of this invention.

As can be readily appreciated by those skilled in the art, bloodpressure of a subject may change from time to time. In critically-illpatients, blood pressure may fluctuate significantly over relativelyshort periods of time such as minutes or even seconds. Heart attack orstroke patients may slip into a cardiogenic shock if the blood pressurefalls below a certain minimum safe value. Rapid detection of fallingblood pressure is important for proper management of such subjects sothat corrective measures are taken as quickly as possible. As bothsystolic and diastolic blood pressure values are typically falling incircumstances of hemodynamic deterioration, it may be possible tofrequently monitor only a systolic or diastolic value in order to detectan event of falling blood pressure. According to the present invention,a LOW BLOOD PRESSURE alarm is initiated when either the systolic ordiastolic blood pressure is detected to be below their correspondingpredetermined low level thresholds. For systolic pressure, this lowlevel threshold may be designated for example to be between 50 and 70mmHg, while for diastolic blood pressure that low level threshold may befor example between 30 and 50 mmHg. The alarm is triggered when eitherof these thresholds is crossed. In addition to detecting rapidly fallingblood pressure, it is important to detect rising blood pressure as itmay among other consequences compromise the limb occlusion state. Upperlimits for systolic and diastolic blood pressures may also be providedand a HIGH BLOOD PRESSURE alarm may be triggered when either thesystolic or diastolic blood pressure has exceeded its corresponding highpressure threshold. Heart rate monitoring may also be optionallydisplayed while detecting the subject's blood pressure.

Using a traditional method of measuring blood pressure requiresdetecting the maximum amplitude of pulsations of the oscillometricenvelope. This in turn requires deflating the cuff at least through apoint of the mean arterial pressure. Doing so during the ischemicduration interval will allow for at least partial reperfusion of thelimb. To avoid this detrimental effect, the present invention providesfor various new methods of detecting systolic blood pressure withoutdeflating the cuff below the limb occlusion pressure.

According to one method of the invention, an initial recoding of thefull oscillometric envelope is made covering the pressure range frombelow the diastolic pressure to above the systolic pressure of thesubject. This can be done during the cuff inflation interval or a cuffdeflation interval in one or several of the preconditioning treatmentprotocol cycles or at other times. The values of A_(MAX), A_(SYS), andA_(DIA) are determined and so are the values of systolic and diastolicpressures. Limb occlusion pressure is then determined using the knowncuff width and length, for example using the following equation:P_(OCCL)=P_(DIA)+(P_(SYS)+P_(DIA))×C/(3×W), where C is limbcircumference and W is bladder width.

The cuff is then inflated by the cuff inflation assembly of thecontroller to an inflated state to initiate the ischemic durationinterval. One method of the invention is based on the assumption thatwhen the blood pressure generally rises or falls, both systolic anddiastolic pressures go up or down. The spread between the systolic anddiastolic values may increase when the blood pressure generally goes upor it can decrease as the blood pressure of the subject generally fallsdown. Frequent surveillance of only either a systolic or diastolic bloodpressure may therefore be used for making a reliable judgment as towhether subject's hemodynamics is compromised or not.

During the ischemic duration interval, the current value of systolicblood pressure of the subject may be determined at least one time duringthe ischemic duration interval. In other embodiments, it is determinedseveral times or on a periodic basis. The frequency of suchdetermination of systolic blood pressure may be about once every minute,once every 30 seconds or even more frequently. In another embodiment ofthe invention, systolic blood pressure is monitored continuously duringat least a portion or preferably the entire ischemic duration interval.Systolic blood pressure is determined by bringing the pressure in thecuff to about the previously detected value of systolic blood pressurebut not reducing it to the value lower than that of the limb occlusionpressure so as not to compromise limb occlusion. The electronics of thecontroller may be programmed to operate the cuff inflation assembly tobring the cuff pressure to a vicinity of a previously recorded systolicblood pressure. A continuously updated segment of the oscillometricenvelope is thereby recorded and compared with the previously obtainedcurve as the cuff pressure is adjusted by the controller—see FIG. 3dotted lines. The new curve may be above, at or below the initiallyrecorded full oscillometric envelope curve or a previously recordedsegment thereof. Since the new segment is recorded within a short timeafter the previous recording, the blood pressure measurementcircumstances do not change appreciably to introduce a significantmeasurement error. Only the changing blood pressure may be assumed tocause the shift in the oscillometric envelope curve. If the curve isfound to be close (within a predetermined margin of error) to theinitial previous curve, the controller is programmed to not change thepreviously recorded values of systolic (and optionally diastolic) bloodpressure. The oscillometric curve is being monitored by the controllerin real time. If the curve is detected to shift up or down, the cuff iscontinued to be deflated (or inflated) by the controller only untilabout the point where the pulsations amplitude is equal with thepreviously recorded A_(SYS) and a correction calculation may beinitiated. The correction calculation includes determining that cuffpressure at which the amplitude of the oscillometric curve is the sameas previously detected A_(SYS), which pressure is then designated as thenew value of systolic blood pressure. The correction also involvesrecalculating limb occlusion pressure and optionally diastolic pressureof the subject. In one embodiment, the new limb occlusion pressure maybe calculated as the new value of systolic blood pressure minus thepreviously known difference between the previous systolic blood pressureand the previous limb occlusion pressure. In another embodiment, the newlimb occlusion pressure is calculated based on the equation above andthe new estimated value of diastolic blood pressure. The new estimateddiastolic pressure may be calculated using predetermined values orslopes for the increase or decrease of the spread between the systolicand diastolic pressures of the subject with a corresponding increase ordecrease in the systolic pressure. Both systolic and diastolic pressures(and optionally a mean arterial pressure and a heart rate) may be shownon a display of the device or transmitted to a conventional display of apatient monitor. The next round of varying or dithering cuff pressure isdone around the newly calculated values. Shifting of the curve segmentupwards indicates an increase in blood pressure while shifting downwardsindicates a drop in blood pressure of the subject.

The above described method needs periodic re-calibration by recording anew full oscillometric envelope curve. During the preconditioningtreatment procedure, full inflation and deflation of the cuff isscheduled at the beginning and the end of every ischemic durationinterval and reperfusion duration interval, which occur every 3-5 min.These events represent convenient opportunities to refresh the fulloscillometric envelope. In one method of the invention, full recordingof oscillometric envelope may be done only during cuff inflations orduring cuff deflations. In another method of the invention, fulloscillometric envelope may be recorded on both cuff inflations and cuffdeflations so as to minimize the time period between such recordings. Inyet other embodiments of the invention, once the LOW or HIGH bloodpressure thresholds are crossed by either the systolic or diastolicblood pressures, the preconditioning treatment protocol is automaticallyinterrupted, an alarm is activated and a full recording of oscillometricenvelope is conducted to confirm the present value of both diastolic andsystolic blood pressure of the subject.

Diastolic blood pressure of the subject may be periodically detectedusing a similar technique as described for systolic blood pressure butduring the reperfusion duration. At least once (or in other embodimentson a periodic basis such as about every 30 or 60 seconds), the pressurein the cuff is raised to about the previously detected or estimatedvalue of the diastolic blood pressure. The new value of diastolic bloodpressure may be detected by matching the amplitude of the newly recordedsegment of the oscillometric envelope with the previously recordedA_(DIA). An upwards shift of the oscillometric envelope segment (shownas dotted line in FIG. 3 in the zone of diastolic pressure) indicates adrop in diastolic and likely a systolic blood pressure of the subject. Adownward shift indicates an increase in blood pressure of the subject.Once the new value of diastolic blood pressure is detected, an updatedvalue of the systolic blood pressure may be calculated and bothpressures may be then shown on a display.

Safe ranges of allowable systolic and diastolic blood pressures arepreselected to trigger a LOW BLOOD PRESSURE or HIGH BLOOD PRESSUREalarms if either the systolic or diastolic blood pressures falls outsidethese respective safe ranges. Using the above described methodologyallows a near-continuous monitoring of the subject's blood pressurebefore, during and/or after the completion of ischemic preconditioningtreatment. Monitoring of systolic blood pressure during the ischemicduration interval coupled with monitoring diastolic blood pressureduring reperfusion duration provides for uninterrupted hemodynamicsurveillance throughout the preconditioning treatment protocol. This isadvantageously done on the same limb, with minimal occlusion of the limbtissue, and without compromising the efficacy of the preconditioningtreatment itself.

In another embodiment of the invention, detecting systolic and diastolicvalues from the segments of the oscillometric envelope recorded in thevicinity of previously detected systolic and diastolic values is done byproviding the controller with a program for analyzing the firstderivative of these segments. A maximum of the first derivative of thesystolic segment indicates a cuff pressure at the systolic bloodpressure of the subject, while the minimum of the first derivative ofthe diastolic segment of the oscillometric envelope may be used toindicate the current value of the diastolic blood pressure. This methodmay be used by itself or in combination with the above or belowdescribed methods to increase the accuracy of detecting systolic anddiastolic blood pressure values.

Bringing the cuff to a minimum limb occlusion state allows detection ofsystolic blood pressure by means and methods other than described abovewhich are based on pure oscillometry. For example, a sensor such as amicrophone or a liquid-filled balloon may be incorporated in the cuff ofthe device of the present invention for monitoring of Korotkoff sounds.Once the sounds are detected, a new value of systolic blood pressure maybe established. The same sensor may be applicable to detecting diastolicblood pressure by cessation of Korotkoff sounds during the periods ofcuff deflation and limb reperfusion. Other sensors may also be used forthis purpose such as for example a plethysmograph sensor, a Dopplersensor, etc.

The controller 150 suitable for the purposes of the present invention isschematically illustrated in FIG. 4. It includes a number of airhandling elements cumulatively forming a cuff inflation assembly andoperable by a central processing unit 120, preferably ASIC-based. Thecuff inflation assembly includes an air pump 140 which may be forexample a diaphragm pump or an air turbine driven by an electricalmotor. Other sources of compressed air or gas may be used for thepresent invention. For example, a cartridge containing compressed air orcarbon dioxide may be used in an all-disposable version of the device.Compressed gas may also be obtained as a result of a controlled chemicalreaction, components for which may be stored in a sealed container priorto use of the device. Wall compressed air may be used on the other handfor a wall-mounted version of the device, such as when used in thehospital. In other embodiments, when the device is a part of acomprehensive patient monitor, its air supply may be adapted to providecompressed air for the device. In a semi-automatic or a manual versionof the device, a manually-operated pump such as a compression bulb maybe used to produce compressed air. Yet, in further embodiments,pressurized liquid may be used to inflate and deflate the bladder of thedevice.

The air pump 140 may be sized to provide a slower rate of cuff inflationas compared with traditional blood pressure measuring devices, which aretypically designed to complete the act of inflating the blood pressurecuff as quickly as possible, frequently in about 10 seconds or less.Traditional blood pressure monitors are designed to finish the procedureof taking a blood pressure reading as quickly as possible so as torapidly provide the reading to the medical practitioner—necessitatingfast inflation of the cuff. Another reason for rapid inflation is toavoid measurement errors caused by motion of the subject.

The remote ischemic preconditioning device of the invention may not beconcerned with these objectives and can be allowed to complete theinflation of the cuff over a longer period of time such as 20, 30, 40seconds or even longer. Slower rate of inflation (preferably less thanabout 0.1 cubic foot per minute) makes it possible to significantlyreduce the size and weight of the air pump 140, the pump driver 141, andthe batteries of the power supply 122 needed for its operation. In oneembodiment of the invention, components traditionally sized for use inwrist blood pressure monitors can be used for inflating the cuff of thepresent invention, which is sized for use with an upper arm of thesubject.

Another advantage of slow inflation is that reliable detection of theoscillometric curve may be less difficult during cuff inflation when airis introduced into the cuff at a slower rate. Variable rate of cuffinflation is also contemplated by the present invention: high cuffinflation rate (such as for example over about 0.1 cubic foot perminute) may be used initially and low cuff inflation rate (such as forexample less than about 0.1 cubic foot per minute) may be used when thecuff pressure reaches blood pressure measurement zones, such as in thevicinity of systolic, mean, and diastolic pressures.

Other elements of the cuff inflation assembly include the pressuresensor circuit comprising a pressure sensor 190 and the pressure readoutunit 191. A vent valve 130 with its driver 131 is provided to vent thecuff bladder to atmosphere. A fast rate of venting or a slow rate ofventing may be provided by the vent valve 130 at different times duringthe procedure of measuring blood pressure. One technique useful foradjusting the rate of venting is pulse-with-modulation of the valve—thevalve may be rapidly opened and closed with adjustable frequency so asto permit variable rate of air therethrough. Fast venting rate may beadvisable during cuff deflation intervals, while slow rate of ventingmay be used during a pressure measurement procedure. Two separate valvesmay also be used for this purpose—a large-bore valve for fast rateventing and a small-bore valve (or a valve connected to a predefined airflow restrictor) may be used for slow rate venting.

The cuff inflation assembly may be operated by a main central processingunit 120, which may in turn be further supplemented by a secondary CPU121. The main function of the secondary CPU 121 may be to monitor theperformance of the main CPU 120 and assure proper opening and closing ofthe vent valve 130. In case of a malfunction of the main CPU 120, thesecondary CPU 121 may be programmed to open the vent valve 131 (dottedline in FIG. 4) to ensure subject's safety.

Other parts of the electronic portion of the controller 150 include thepower supply 122, the user input 124, and the display 126. When thedevice of the invention is incorporated into other devices such as acomprehensive patient monitor, these elements and their functions may beprovided by corresponding elements of the patient monitor. In case of adedicated controller configured for preconditioning and pressuremonitoring function of the stand-alone version of the present invention,the power supply 122 includes batteries, preferably primary lithiumbatteries with long shelf time. Wall outlet power or rechargeablebatteries are also contemplated as useful energy sources.

When the controller 150 is operated properly during the course of theischemic preconditioning treatment protocol, the main CPU 120 isprogrammed to start, adjust the speed and stop the electrical motoroperating the air pump 140; cause properly timed opening and closing ofthe vent valve 130 via operating a vent driver 131; and to record andprocess the pressure signal using the pressure sensor 190 and thepressure readout unit 191. All these operations are cumulativelyreferred to by the terms “inflating the cuff”, “deflating the cuff”, or“bringing the cuff to a certain pressure” as used above and belowthroughout this description.

In one useful configuration of the device, the user input 124 is asingle START button. In a fully automatic version of the device, oncethe cuff is placed about the limb of the subject, pushing this buttonmay start the ischemic preconditioning treatment protocol so no furtheraction is required from the user. Progression of the treatment may becommunicated to the user by a display 126. Other user input buttons thatmay be optionally provided including an “Emergency deflate” and “Resume”buttons. These buttons are useful to allow the medical practitioner tointerrupt the treatment protocol. The functionality of these buttons mayalso be designed into the above mentioned START button. For example,depressing and holding the START button during the treatment mayinterrupt it. Pressing it again after such interruption will cause theprotocol to be resumed. The controller 150 may be configured in thiscase to resume the interrupted cycle from the beginning or repeat theentire treatment protocol if the interruption delay has been longer thanallowed, such as for example 10 min or more. One advantage of designingthese functions into the START button is to make the user interface assimple as possible by only providing dedicated buttons for frequentlyused functions, such as a single START button for example.

The main CPU 120 and display 126 of the controller 150 may additionallybe programmed to start a 1- or 2-hour countdown at the end of theischemic preconditioning treatment protocol. As the first window ofischemic preconditioning effect has limited duration of 1-2 hours, it iscritical to restore blood flow to the ischemic organ within that generalperiod of time. The display may include a time countdown segment toadvise the user of progression of that time period. If reperfusion ofthe ischemic organ is not accomplished within that timeframe, thetreatment may have to be repeated later and completed preferably justprior to expected reperfusion of the ischemic organ. One situation whenthis may be the case is when a heart attack patient is brought to thefirst hospital which is not equipped for percutaneous interventions. Atransfer to the second hospital having such capability may cause aprolonged delay. The device of the invention may be configured to allowfor a second ischemic preconditioning treatment, which may be timed tobe completed at the time of arrival to this second hospital or shortlythereafter.

A disposable version of the device of the invention may be furtherconfigured to limit the number of operating hours or the number oftreatments the device is allowed to deliver so as to prevent further useand ensure the proper function of the batteries. Initial activation ofthe device may be accomplished by pulling out a tab to connect batteriesto the controller 150. Once activated, the device may be limited as tohow long it stays active using one of the protocols as described below:

-   -   Up to about 40 min for one 4-cycle procedure—device may be        permanently disabled thereafter and only allowed to support a        2-hour reperfusion countdown on its display;    -   40 min+2 hours reperfusion countdown+40 min+2 hours countdown        for two ischemic preconditioning treatments back to back;    -   40 min+2 hours countdown+up to 10 hours of stand-by+40 min+2        hours countdown for two procedures—useful when the first        procedure and the first 2-hour window did not result in        reperfusion, the second procedure may be done up to 10 hours        later and just before the second reperfusion attempt        (example—transfer of patient to a second hospital);    -   Up to 12 or 24 hours fixed operational time—allows using the        device both prior and past the PCI or thrombolysis procedure for        delivering one or several preconditioning treatment protocols        before and after the reperfusion of the ischemic organ.

Other optional features may include a manual user input capability toenter a user-selected limit of cuff inflation pressure. If the devicecannot detect the blood pressure of the subject, an override may beincluded allowing the user to select the upper level of cuff inflation.The function of the device may be limited in this case as no automaticmonitoring of hemodynamics would be conducted. At the same time, theprimary purpose of the device, namely providing ischemic preconditioningwill still be enabled.

In another embodiment, the device of the invention may be configured tobe used as a hybrid blood pressure measuring device. The user input unit124 will in this case additionally include a SYSTOLE and DIASTOLEbuttons. During the process of taking a blood pressure reading, themedical practitioner may inflate the cuff (activating the air pump 140or manually) to a pressure above an estimated systolic pressure and thenactivate a slow deflation of the bladder while listening for Korotkoffsounds with a stethoscope. Once the first sound is detected, a SYSTOLEbutton is pressed. The device may be configured to record and displaythe instant pressure reading from the pressure sensor 190 at the timethe SYSTOLE button is pressed as the systolic pressure of the patient.The gradual deflation of the bladder is then continued and when the lastKorotkoff sound is heard, the medical practitioner presses a DIASTOLEbutton freezing the instant reading from the pressure sensor 190 as adiastolic pressure of the patient. The device may be then configured torely on these blood pressure measurements to conduct the preconditioningtreatment protocol as described above but without further hemodynamicsurveillance.

Dual-Bladder Device for Remote Ischemic Preconditioning

FIGS. 5 and 6 pertain to a dual-bladder embodiment of the presentinvention. Having more than one bladder allows a more accurate detectionof systolic and diastolic blood pressure values of the subject. Whenonly one bladder is used, occlusion of the arterial blood flow throughthe limb may be primarily accomplished in the middle portion of thebladder. The upper or proximal portion of the bladder invariably has asection where the artery is only partially occluded. This causes a lowlevel of pulsations to be still present on the cuff pressure curve evenat cuff pressures above the limb occlusion pressure and even further atpressures above the systolic blood pressure of the subject. This createsa situation when complete occlusion of the limb does not entirelydepress cuff pulsations making it difficult to accurately detect thelevel of systolic blood pressure. One way to address this probleminvolves using various above-described empirically-derived methods ofdetermining systolic and diastolic blood pressure values. The limitationof these methods is that they rely on statistically-derived averageratios of pulsation amplitudes. Such average ratios may not be entirelyaccurate for all patients. It is desired therefore to actually measurethe values of systolic and diastolic blood pressures rather thancalculate them based on a measured mean arterial pressure. It is furtherdesirable to provide these measuring methods without jeopardizing thepreconditioning treatment efficacy. In other words, it is desirable tomeasure systolic blood pressure during the ischemic interval withoutallowing for reperfusion. It is also desirable to measure the diastolicblood pressure during reperfusion duration without significantlyobstructing blood flow through the limb.

The cuff 210 of the dual-bladder embodiment includes a first bladder 212(designated here as a proximal bladder—that which is closer to theheart) and an opposing second bladder 213 (designated here as a distalbladder—that which is further away from the heart). In anotherembodiment, both bladders are located adjacent or next to each other. Toassure a snug fit over the limb of the subject, both bladders may bejoined together only along a portion of their circumference. Separatedends of the cuff are envisioned to be individually wrapped about thelimb of the subject to provide a tight fit over a curved limb. Inflatingboth bladders to a pressure at or above the limb occlusion pressure willact to substantially occlude the limb as if with a single bladder havinga total width equal to the sum of widths of the proximal and distalbladder, W=W_(P)+W_(D). The bladder circumference L may be also selectedto be equal between the proximal bladder 212 and the distal bladder 213so as to assure an even compression of the limb when both bladders areinflated to the same pressure. Both bladders in that sense can be viewedas two parts of a single wide bladder. The combined bladder width andbladder length of the cuff in this embodiment may follow therecommendations and sizes described above for the single-bladderembodiment of the invention.

In one aspect of the invention, while the total width of both bladdersmay be made to cover substantially the entire length of the limb such asthe length of the upper arm, the width of one of the bladders (such asthe proximal bladder 212 for example) may be made to follow standardsizing of blood pressure measuring cuffs as described above. Given thelimitation of the total available length of the limb, this makes thedistal bladder 213 narrower than the proximal bladder 212. Having atleast one of the bladders with a standard cuff width allows using thatbladder for traditional manual or automatic oscillometric blood pressuremeasurement. Such traditional blood pressure measurement may be used incombination with the results obtained using the methods described inthis disclosure to assure its accuracy and improve its reliability. Forexample, when a measurement error or inability to measure blood pressureusing some methods of the invention are detected by the controller ofthe invention, it may be configured to revert to traditionaloscillometric measurement to still obtain blood pressure data.

The controller 250 is illustrated schematically in FIG. 6. Only the airhandling components forming the cuff inflation assembly are shown inFIG. 6. The electronic components including the central processing unitare similar to that described above for controller 150 and therefore arenot shown. Each bladder may be generally inflated and deflated via itsown dedicated air handling circuit. The proximal bladder 212 may beinflated by the air pump 240 when it is connected by the controller tothe bladder via activating an on/off valve 276. Gradual deflation ofthis bladder may be accomplished by the controller programmed to openand close at appropriate times a vent valve 272 while the pressure inthe proximal bladder may be monitored by a pressure sensor 274. Thedistal bladder 213 may be inflated the controller opens the on/off valve266 and activates the same air pump 240. It may be deflated by thecontroller by opening the vent valve 262, and monitored by the pressuresensor 264. This arrangement allows for both independent or simultaneousinflation and deflation of bladders 212 and 213. It also provides forredundancy in operation whereby increasing the safety of the device. Forexample, if one of the vent valves malfunctions and cannot be opened,both bladders may still be deflated by opening the other vent valve aswell as both valves 266 and 276. Cross-checking or equilibrating ofpressure in the bladders may also be possible by the controller causingopening of both valves 266 and 276.

Prior to, during or after the preconditioning treatment protocol, one orboth bladders 212 and 213 may be used to periodically measure bloodpressure of the subject. Such measurement may be taken on inflation ordeflation of the bladders. Assuming measurements on cuff deflation, anovel blood pressure measurement procedure would include the controller250 causing inflation of at least the proximal bladder 212 to a pressureexceeding a previously measured or estimated systolic blood pressure ofthe subject. The distal bladder 213 may then be inflated by thecontroller operating the cuff inflation assembly to a pressuresufficient to monitor arterial cuff pulsations caused by heart ratepulsatility. As maximum amplitude of pulsations in either bladder isexpected to be detected by the controller 250 around the point of meanarterial pressure, in one method of the invention, the distal bladder213 may be inflated to a previously measured or estimated mean arterialpressure. This pressure setting is advantageous when measuring bloodpressure in subjects with weak or difficult to detect pulsations of thecuff pressure. Yet, in another method of the invention, the distalbladder 213 may be inflated by the controller 250 to the same orslightly lower pressure as that of the proximal bladder 212 so as tocontribute to the overall occlusion of the limb during or after theblood pressure measuring procedure. The pressure in the proximal 212 anddistal 213 bladders may then be gradually decreased by the controller250 opening the vent valves with the distal bladder 213 having apressure not exceeding that of the proximal bladder 212. Once thepressure in the proximal bladder 212 is at or below the level ofsystolic blood pressure, the amplitude of pulsations in the distalbladder 213 undergoes a rapid increase, at least by 20% or more, fromthe previously detected level. In some patients, this amplitude mayreach 2 to 10 times that of the previous level. This rapid or suddenincrease is caused by arterial pulsations no longer prevented by theproximal bladder 212 from reaching the distal bladder 213. Simultaneousor alternating pressure monitoring in both bladders allows detection ofthe pressure point in the proximal bladder 212 corresponding with anincrease in the amplitude of pulsations in the distal bladder 213. Thisproximal bladder pressure may then be designated by the controller 250as the systolic blood pressure of the subject. The pressure in theproximal bladder 212 may be optionally increased and gradually decreasedagain at least one or more times so as to cross the systolic bloodpressure point repeatedly to collect additional measurement points. Anaverage reading may then be calculated so as to reduce the impact ofmeasurement artifacts. This reading may then be displayed for the useron a display of the device.

Once the systolic blood pressure is identified, continuing deflation ofproximal and distal bladders may be used to detect the diastolic bloodpressure. When the pressure in both bladders is between the diastolicand systolic values, the amplitude of pulsations in the proximal bladder212 would be generally higher than pulsations in distal bladder 213 asthe proximal bladder 212 would impart certain blood flow restriction andtherefore dampen the magnitude of pulsations in the distal bladder 213.It is further suggested that once the pressure in the proximal bladder212 has reached the distal blood pressure, both bladders would havepulsations of similar and reduced magnitude, as there would be no morerestrictions on the blood flow through the limb. The pressure value inthe proximal bladder 212 at which the amplitude of pulsations in bothbladders have reached a comparable level (such as within 10% of eachother) may be used as a point where diastolic blood pressure isdetected. In other embodiments of the invention, the pressure in eitherbladder when pulsations amplitude has dropped to a predetermined levelor has dropped rapidly as compared with the previous level (such as by20% or more) may be used to indicate the diastolic blood pressure of thesubject.

The general dual-bladder blood pressure measuring procedure describedabove may be adapted to be conducted by the controller 250 during theischemic preconditioning treatment protocol without compromising itsefficacy. At the beginning of at least one preconditioning cycle or inother embodiments at the beginning of each preconditioning cycle, bothbladders 212 and 213 are caused by the controller 250 to be inflated toa pressure at or above the previously determined or estimated value oflimb occlusion pressure. In one preferred method of the invention, theproximal bladder 212 may then be inflated to a pressure above thatpreviously measured or estimated systolic blood pressure of the subjectwhile the distal bladder 213 may be kept at a pressure between the limbocclusion pressure and the systolic blood pressure. The pressure in theproximal bladder 212 may then be gradually reduced until a sharpincrease in pressure pulsations in the distal bladder 213 is detected soas to indicate the new value for systolic blood pressure. Having the newvalue of the systolic pressure allows calculating the new value of limbocclusion pressure using the known width and length of the cuff. Bothbladders may be then inflated by the controller 250 to a pressure atleast equal or above the newly calculated limb occlusion pressure andoptionally close to or higher than the newly detected systolic bloodpressure. Periodic repeating of systolic blood pressure detectionprocedure may be used for hemodynamic surveillance. Periodicity ofrepeating the blood pressure determination procedure may be at leastonce during each ischemic duration interval. In other embodiments,systolic blood pressure is measured once about every 30 to 60 seconds.In yet another embodiment of the invention, the pressure in the proximalbladder 212 may be continuously adjusted or dithered by the controllerto fluctuate about the systolic blood pressure so as to monitor itschange essentially on a continuous or near-continuous basis. Thisapproach has an advantage of providing an additional monitoringmodality, namely monitoring the rate of increase or decrease of systolicblood pressure. An additional alarm may be activated when the systolicblood pressure is seen to experience a rapid rate of decrease—evenbefore the actual value has reached an allowed safe threshold.

Importantly, throughout the entire ischemic duration interval, thepressure in either bladder may not be allowed by the controller 250 todrop below the most recent known value of the limb occlusion pressure soas not to compromise the efficacy of ischemic preconditioning treatment.

During the limb reperfusion duration, a similar but “reversed” bloodpressure measurement procedure may be conducted by the controller 250 ona periodic basis to detect the diastolic blood pressure of the subject.In one embodiment of the invention, during at least a portion of thereperfusion duration both bladders are inflated by the controller 250 toa level about the previously detected or estimated diastolic bloodpressure of the subject. The new diastolic blood pressure is detectedwhen the distal or proximal bladder has pulsations amplitude equal tothat measured previously for diastolic pressure. In another embodiment,the diastolic pressure is indicated by a proximal cuff pressure valueassociated with a rapid drop in pulsation amplitude of the distalbladder.

In its most comprehensive form, the method of the present inventionallows for continuous monitoring of the blood pressure of the subjectthroughout the entire ischemic preconditioning treatment protocolwithout compromising its efficacy and without requiring the use ofanother limb for monitoring purposes. Systolic blood pressure in thiscase is measured by the controller using one of the above describedmethods during the ischemic duration interval followed by an optionalcalculation of estimated diastolic blood pressure. During reperfusionduration, the diastolic blood pressure is measured as well on anear-continuous or periodic basis, followed by an optional calculationof an estimated systolic blood pressure of the subject. One or bothsystolic and diastolic blood pressure values are presented on a displayof the device.

For patients with a weak pulse, an additional improvement contemplatedto be within the scope of the present invention may be an artificialpulse generator located at the proximal portion or above the proximalbladder of the device. Such pulse generator may be a narrowrapidly-inflatable third bladder or a mechanical artery-compressionmeans. Activation of this pulse generator causes a series of arterycompressions. Depending on the degree of limb compression by theproximal bladder, these pulsations may or may not reach the distalbladder. The proximal bladder pressure at which these pulsations nolonger reach the distal bladder is designated as a systolic pressure ofthe subject. To further improve the accuracy of pressure detection, theintervals between the pulsations of the artificial pulse generator maybe uneven so that the device can easily discern between the natural andartificial pulse.

The above described methods for detecting blood pressure are conductedduring gradual deflation of the proximal bladder 212. To conduct thepressure measurement on inflation of this bladder, another method of thepresent invention includes the steps of inflating the distal bladder toat least a pressure point when its pressure pulsatility may be reliablydetected. The proximal bladder 212 may then be inflated to that samepressure and then continued to be inflated (optionally with a slowerrate of inflation) until a rapid decrease in pressure pulsatility isdetected in the distal bladder 213 indicating that the pressure in theproximal bladder has reached a systolic pressure. The pressure in thedistal bladder 213 may then be increased to match that of the proximalbladder 212. Inflation of both bladders may be done at the same timeaccording to another method of the invention.

A simplified version of the device is provided in yet another embodimentof the invention in which the controller may include two or only onepressure sensor, which may be connected at first or permanently tomonitor pressure in the distal bladder. The controller is programmed fordelivery of ischemic preconditioning treatment protocol as describedabove. The novel feature in this embodiment is the method of cuffinflation including inflating both bladders to a first pressuresufficient to detect pressure pulsations in the distal bladder and thento a second pressure to detect a rapid decrease in the amplitude of suchpulsation.

The controller in this embodiment may be programmed to first causeinflation of the distal bladder to a first pressure at which pressurepulsations are clearly detected in the distal bladder. The proximalbladder may be inflated to the same first pressure in parallel with theinflation of the distal bladder or after the distal bladder is alreadyinflated to the first pressure. Once the pressure pulsations areidentified in the distal bladder, the bladders are inflated (in parallelor starting with a proximal bladder first) to a second pressure when theamplitude of pressure pulsations in the distal bladder rapidlydecreases, whereby defining systolic pressure of the subject.Optionally, inflation from the first pressure to the second pressure maybe done at a slower inflation rate. This second pressure is sufficientto maintain limb occlusion throughout the ischemic duration interval.During cuff deflation, both bladders are deflated to or below the firstpressure to allow for limb reperfusion. To separate pressure signals ofone bladder from another in order not to contaminate the pressure signalof the distal bladder with the noise from the proximal bladder, acalibrated air flow restrictor may be positioned in an air line betweenthe bladders. In another embodiment, a valve separating one bladder fromanother is installed. It may be operated by the controller tointermittently isolate and then reconnect two bladders so that pressuremonitoring in the distal bladder can be done during periods ofseparation of the bladders. Reconnecting bladders together allowsequalizing pressure in both bladders.

One advantage of this embodiment is that the level of cuff inflation(the second pressure) is defined at the beginning of each cuff inflationinterval and therefore may track the changes in subject's bloodpressure.

After the completion of the ischemic preconditioning treatment protocol,the device of the invention may be configured to resume the bloodpressure monitoring mode as described above and to initiate a 1- or2-hour countdown indicating the time available for reperfusion without aloss of the preconditioning effect. This mode may be particularly usefulafter completion of percutaneous intervention while the subject istransferred from the catheterization laboratory to the step-down unit.

Ischemic Preconditioning Devices for Use in a Percutaneous InterventionSetting

Release of emboli during a percutaneous intervention can cause harmfuleffect downstream of the point of such release. It is known for examplethat elective percutaneous coronary intervention (PCI) proceduressometimes cause significant elevation in the level of Troponin and otherinfarct-indicating enzymes. This is believed to be a result of releaseof microembolic particles at the site of stenosis and stentimplantation, these particles causing a number of obstructions insmaller arteries downstream. Carotid percutaneous interventions areknown to sometimes exhibit a similar effect on the brain tissue.

In view of this risk, all percutaneous procedures may benefit fromremote ischemic preconditioning treatment. Recent studies withmanually-delivered ischemic preconditioning using a simple bloodpressure cuff have confirmed such benefit for elective PCI patients asmeasured by reduction in Troponin release at 24 hrs after the procedure.As maximum benefit is derived when ischemic preconditioning is completedjust prior to such percutaneous intervention, provided herein aredescriptions of the novel device of the invention adapted to be used inthe catheterization laboratory environment.

Inserting a catheter percutaneously requires making an opening in anartery, typically in a femoral artery. After the percutaneousintervention procedure is finished, this arterial opening has to bereliably closed to avoid postprocedural bleeding. Various invasive andnon-invasive devices are available on the market to accomplish thispurpose. The recent trend in vascular sealing is to avoid highlyinvasive closure device acting on the arterial site itself. Non-invasiveor minimally invasive devices providing overall compression of theinsertion site are gaining in popularity due to their simplicity andease of use.

The novel device of the present invention is a combination device forischemic preconditioning and vascular sealing. It may be first appliedto deliver a series of limb occlusions for the purposes of ischemicpreconditioning and then reapplied again after the completion ofpercutaneous intervention to cause extended tissue compression for thepurposes of external vascular sealing. The device may be configured tobe used on either an arm or a leg of a subject. In one embodiment of theinvention, the device is adapted for femoral puncture site closure.

According to another embodiment (not shown on the drawings), the deviceof the invention includes a single occlusion bulb designed and sized toocclude the target artery such as a femoral artery. It can be retainedover the arteriotomy by a retaining means such as an adhesive sheet, abelt, attached to a cuff wrapped about the thigh, or a surrounding clampwrapped about the patient. Once the bulb is positioned over the futurearteriotomy site before the procedure, it may be periodically inflatedand deflated by a controller to cause ischemic preconditioningocclusions of the leg according to a predetermined ischemicpreconditioning treatment protocol. Such treatment protocol may includea predetermined number of ischemic duration and reperfusion intervalssimilar to what is described above. Optional monitoring of distalperfusion or distal oxygenation may be used to ensure full arterialocclusion, for example a pedal Doppler or a pulse-oxymeter. Uponcompletion of the ischemic preconditioning procedure, the bulb may belifted or entirely moved out of the way to allow for femoral access andcatheter insertion. The device includes provisions to easily return thebulb to the same original position later after the percutaneousprocedure is finished. One practical way to achieve this may be to leavein place the main retaining means of the bulb on the patient's limb(adhesive tabs or a retaining belt) and provide additional detachingmeans to move only the bulb itself from its original position and tostore it off the arteriotomy site. When the catheterization procedure isfinished and the catheter is removed from the artery, the bulb may bereturned to its original position. Optionally, the bulb may be equippedwith a removable cover. Taking the cover off allows exposing a newsterile surface towards the wound after returning the bulb to thearteriotomy site. Reinflation of the bulb provides for tissuecompression causing hemostasis and vascular sealing. In anotherembodiment of the device, after initial firm compression of thearteriotomy for a predetermined period of time such as 5 to 10 min orso, the controller may be configured to partially deflate the bulb. Thiswill allow at least some blood flow past the arteriotomy. Thereafter thebulb may be gradually or periodically deflated again by the controllerin predetermined increments of volume or pressure reduction so as togradually decrease the tissue compression above the arteriotomymimicking the manual hemostasis procedure.

A further configuration of the device 300 (see FIGS. 7-10) involves twoinflatable bulbs or bladders—a first bladder 321 incorporated into apreconditioning cuff 320 and the second bladder 312 included in avascular sealing subassembly 310. In one embodiment, this configurationincludes a preconditioning cuff 320 sized according to the standardthigh cuff sizes described above. In another embodiment, the cuff 320 issized to cover as much of the thigh length as possible so as to reducesubject's pain and discomfort. It also may further include a proximalbladder and a distal bladder as described above configured for bloodpressure monitoring in addition to ischemic preconditioning. Cuffclosure means (not shown), for example Velcro are provided to ensure asnug adjustable fit over the subject's limb. When the cuff 320 may bewrapped around the thigh of the subject and the bladder 321 is inflatedto a sufficient pressure (at least a limb occlusion pressure) by thecontroller 330 (which can be configured using any of the above describedconcepts), blood circulation to the thigh is interrupted. Attached tothe preconditioning cuff 320 via an adjustable-position attachment means340 (described below in more detail) is an inflatable vascular sealingassembly 310 with a second bladder 812. This bladder may be sized andpressurized to provide for full occlusive pressure over the femoralartery or only for maintaining hemostasis which is first achieved usinga manual compression or another device-assisted technique. Thecontroller 330 may be designed as a disposable or reusable part. It maybe connected to both the preconditioning bladder 321 and the vascularsealing bladder 312 via independent attachment channels such as a dualchannel tube 350 and/or internal air passages formed within otherelements of the device (not shown).

The controller 330 may be configured to provide dual functionality ofdelivering ischemic preconditioning as described above and the vascularsealing capability to properly inflate, monitor, adjust if needed andgradually deflate the vascular sealing bladder 312. One advantageousnovel method of operating the vascular sealing bladder 312 is toinitially fully inflate it to sufficient pressure to cause fullcompression of the artery in order to establish initial hemostasis. Thecontroller 330 may be configured to then deflate the bladder 312 atpredetermined intervals of time or using predetermined graduallydecreasing pressure levels. Another method of operating the bladder 312is to use the preconditioning bladder 321 located on the thigh of thesubject as a pressure sensor.

Above described methods of monitoring systolic and diastolic bloodpressure values may be used in this configuration to allow detection ofblood flow past the vascular sealing bladder 312. Flow detection methodsmay include operating both bladders as described above for thedual-bladder device, in which case the preconditioning bladder 321 maybe inflated partially and treated as a distal bladder 213. In that case,following the initial full inflation of the vascular sealing bladder312, complete occlusion of flow will be initially confirmed and thencontinuously indicated by the lack of pulsations or Korotkoff sounds asdetected by monitoring pressure patterns in the preconditioning bladder321. After a specified period of time, for example 5 to 10 minutes, agradual deflation of the vascular sealing bladder 312 may be initiatedby the controller 330 until a rapid increase of pulsation amplitude (orthe presence of Korotkoff sounds) is detected in the preconditioningbladder 321 indicating restoration of at least a partial flow in thefemoral artery. The next step may be deflating the vascular sealingbladder 312 until reduction in pulsation amplitude or cessation ofKorotkoff sounds indicating restoration of full flow in the limb artery.At this point, the tissue around the artery is still compressed allowingfor maintaining hemostasis. Thereafter, the vascular sealing bladder 312may be further deflated and eventually removed from the patient.Additional intermittent points in deflation of the vascular sealingbladder 312 are also envisioned to further delay reduction ofcompressive force on the site of arteriotomy. At the end of the abovedescribed gradual or incremental deflation process, an optional alarmmay be turned on by the controller 330 to attract the attention of amedical practitioner to the fact that the vascular sealing is complete.Adjustable user-selected programs or intervals of periodic deflation maybe incorporated into the controller 330 so as to accommodate variousclinical situations such as an obese person, or various levels ofanticoagulation in the blood stream of the subject. These situations maybe handled by switching from one predetermined deflation program toanother. Manually set deflation intervals are further envisioned toprovide the medical practitioner with needed discretion in using thedevice of the invention.

Adjustable-position attachment means 340 between the vascular sealingsubassembly 310 and the ischemic preconditioning cuff 320 are nowdescribed in more detail. Attachment means 340 have to satisfy thefollowing main functional requirement: allow for storage of the vascularsealing bladder 312 near or over the ischemic preconditioning cuff 320in the least obtrusive way so as to minimize its protrusion above or tothe side of the preconditioning cuff 320 during the ischemicpreconditioning procedure. At the same time, after the completion ofpercutaneous catheterization procedure, the attachment means 340 shouldallow extension of the sealing subassembly 310 to the arteriotomy siteand sufficient support of the vascular sealing bladder 312 when inflatedso as to compress tissue over arteriotomy to achieve hemostasis.Importantly, this invention provides for a novel means of supporting thevascular sealing bladder 312 over the site of the arteriotomy, namely ausing the preconditioning cuff 320 wrapped about the subject's thigh,the cuff 320 equipped with the vascular sealing bladder attachment means340. This is different from other known devices which rely either on askin adhesive or on a surrounding clamp wrapped about the subject'sbody.

FIG. 9A shows a top view of one embodiment of the device of theinvention presented in its collapsed configuration. The preconditioningcuff 320 includes a bladder 321 and a pocket comprising a wide section322 sized to accept a vascular sealing subassembly 310. The pocket alsocontains a narrow long section 323 (optionally reinforced or made from arigid material) sized to snuggly accept the attachment means 340.Attachment means 340 in turn comprises in one aspect of the invention amalleable member 311. Deployment of the sealing subassembly 310 may beachieved by partial extending it from the pocket 322 and bending themalleable member 311 so that the vascular sealing bladder 312 ispositioned over the arteriotomy. Expanded configuration of the device isshown in FIG. 9B. Alternate configurations includes storing the vascularsealing subassembly 310 with the attachment means 340 separately andthen attaching it to the preconditioning cuff 320, for example byinserting a member 311 into the pocket 323.

FIG. 10 shows an expanded configuration of another embodiment of thedevice of the invention. Attachment means 340 allow for rotating thevascular sealing subassembly 310 from its storage position over thepreconditioning cuff 320 to its operating position as shown in FIG. 10using a rotating joint 347. Optionally, the joint 347 includesprovisions (such as a ratcheting mechanism) allowing only one-waymovement of the subassembly 310 in the direction of the arrow in FIG.10. This precludes it from moving back towards it storage position. Anoptional release button may further be provided (not shown). Althoughrotation in a vertical plane is shown in FIG. 10, other orientations ofthe rotation plane for joint 347 are also envisioned including ahorizontal and tilted orientation. Additionally, joint 347 allows foradjustment of the bulb position to the left or to the right from thecuff when viewed from above.

Attachment means 340 may additionally include provisions allowingextending the position of the bladder 312 lengthwise and away from thecuff 320. One or two sliding joints are provided for this purpose. FIG.10 shows a first sliding joint comprising a tube 345 and a rod 346 and asecond sliding joint comprising a tube 348 and a rod 349. These jointsare designed to provide for sufficient range of length extension withoutcompromising the strength of retaining the vascular sealing subassembly310 by the cuff 320 over arteriotomy.

The sealing subassembly 310 comprises a vascular sealing bladder 312attached to a disk 313 and optionally covered by a removable cover 314to allow a sterile surface of the bladder 312 to be exposed towards thewound when the bladder 312 is placed over the arteriotomy site.

In another aspect of the invention, the attachment means may include oneor two swivel joints and an extension member. The swivel joints may bemade to include tightening clamps so as to retain their position. Thisembodiment provides an ability to reposition the vascular sealingsubassembly from time to time by loosening and tightening clamps of theswivel joints. The presence of the swivel joints is also helpful inadjusting the angle between the occluding bladder and the skin so as toallow placing the bladder flat on the skin irrespective of the tissuecurvature.

A Sheath Equipped for Ischemic Preconditioning for Use During aCatheterization Procedure

FIG. 11 shows yet a further embodiment of the device of the inventionadapted for use during a percutaneous intervention. It illustrates anintroducer sheath configured for delivering of an ischemicpreconditioning therapy prior, during, or after a catheterizationprocedure. The introducer sheath 400 of the invention comprises a sheathtube 410 extending from a hub 420. An inflatable occluding balloon 440made for example from an elastic material such as silicone or latex maybe located at the distal end of the sheath tube 410. Inflation of theballoon 440 can be accomplished by injecting air or liquid (such assaline) through a lumen 450, which may in turn be connected to anexternal controller (not shown). The balloon 440 may be sized to occludethe artery in which the sheath 400 is inserted. The balloon 440 may befurther designed to have a low profile when deflated so as not toincrease the thickness of the sheath tube 410. Other embodiments of theinvention include means for mechanical expansion of a distal portion ofa tube 410 which will accomplish the same result of occluding theartery. An intervention catheter 430 may be introduced through a sheath400 using commonly known insertion techniques.

The controller may be configured to inflate and deflate the balloon 440according to an ischemic preconditioning treatment protocol as describedabove, for example having 3-4 cycles of 3-5 min inflations and 3-5 mindeflations. The controller may be designed as a reusable electronicdevice similar to that described above but sized to inject a smalleramount of air or liquid (saline) to inflate the balloon 440. In anotherembodiment, the controller may be made as a disposable attachment to thesheath 400 allowing for a semiautomatic operation of the device. Thecontroller in that case may include one or more inflatable chambers thatare pressurized all at the same time when filled by a syringe before thebeginning of the percutaneous intervention procedure. An electrically-or mechanically-activated communication system may be provided toconnect one chamber at a time to balloon 440 so as to cause inflationthereof. After a predetermined period of time, the balloon 440 may bevented to atmosphere or exposed to vacuum causing its deflation.

Additional useful provisions for the device of the invention includeindicators of proper balloon inflation. Total occlusion of the arterymay be monitored manually or with known devices to assess distal pulse.Lack of distal pulse indicates proper balloon inflation. An optionalindicator window (not shown) may be incorporated in the hub 420 which inturn may be connected with an arterial opening close to the location ofthe balloon 440 but spaced a short distance towards the hub. Underarterial pressure, a pulsating blood meniscus may be visible through thewindow. Inflating the balloon 440 and occluding the artery may beconfirmed by cessations of these pulsations. Deflation of balloon 440may be verified by resuming pulsations of blood meniscus through thewindow.

In use, the sheath 400 may be inserted in the arterial system of thesubject at the beginning of catheterization procedure which is thencarried out as usual. During the intervention procedure, the side armlumen 450 is attached to the controller and the balloon 440 may beoperated to cause ischemic preconditioning in the patient's limb. Afterthe catheterization procedure and ischemic preconditioning procedure arecomplete, the sheath may be withdrawn in a usual manner. This device ofthe invention allows for easy and seamless delivery of ischemicpreconditioning during the percutaneous intervention procedure withoutthe need to finish preconditioning before revascularization.

In another aspect of the invention, a dual-lumen introducer sheath ofthe invention is provided with a generally oval or egg-likecross-sectional shape. This cross-sectional shape will allowincorporating the balloon inflation lumen without compromising thecircular main segment of the sheath and with minimizing the trauma tothe artery. In another embodiment of the invention, the sheath ispositioned in the artery with the long axis of the oval or egg-likecross-sectional shape oriented orthogonally to the longitudinal axis ofthe artery. This orientation will provide for the least disturbance tothe media layer of the artery, containing arterial contraction muscles.

The concept of building an ischemic preconditioning element into anexisting percutaneous device described above may be expanded beyond theintroducer sheath to other catheters and delivery systems. One exampleof such system is a delivery device for a stent-graft device used duringa percutaneous treatment or an aortic or abdominal aneurysm. As ischemicpreconditioning treatment may be useful for patients undergoing theseprocedures. Incorporating a preconditioning expandable balloon within astent delivery system at a projected location of femoral or iliac arterymay facilitate delivering of preconditioning benefits to a broad groupof patients.

Although the invention herein has been described with respect toparticular embodiments, it is understood that these embodiments aremerely illustrative of the principles and applications of the presentinvention. It is therefore to be understood that numerous modificationsmay be made to the illustrative embodiments and that other arrangementsmay be devised without departing from the spirit and scope of thepresent invention as defined by the appended claims.

I claim:
 1. A device for remote ischemic preconditioning, the devicecomprising: a cuff sized to retract about a limb of a subject, acontroller connected to said cuff, said controller configured to inflateand deflate said cuff according to a remote ischemic preconditioningtreatment protocol, said treatment protocol includes at least twosequentially performed treatment cycles, each of said treatment cyclescomprising: inflating said cuff to a cuff pressure at or above a limbocclusion pressure of the subject, maintaining said cuff pressure at orabove said limb occlusion pressure for a period of at least about oneminute, and deflating said cuff for at least about one minute to restoreblood flow in said limb, wherein during maintaining said cuff pressureat or above said limb occlusion pressure, said controller is furtherconfigured to vary said cuff pressure at least once after apredetermined period of time during at least one of said treatmentcycles.
 2. The device as in claim 1, wherein said controller is furtherconfigured to detect a systolic blood pressure of the subject duringvarying of said cuff pressure.
 3. The device as in claim 2, wherein saidcontroller is further configured to inflate said cuff pressure to avicinity of a previously recorded systolic blood pressure during varyingof said cuff pressure.
 4. The device as in claim 3, wherein saidcontroller is further configured to determine a diastolic pressure ofthe subject, whereby said subject is under continuous hemodynamicsurveillance throughout said ischemic preconditioning treatment.